Table Of ContentChi-HueyWong(Ed.)
Carbohydrate-based DrugDiscovery
Carbohydrate-basedDrugDiscovery.EditedbyChi-HueyWong
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30632-3
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Chi-Huey Wong (Ed.)
Carbohydrate-based Drug Discovery
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V
Contents
Volume1
Preface XXV
ListofContributors XXVII
1 SyntheticMethodologies 1
ChikakoSaotomeand OsamuKanie
1.1 Introduction 1
1.2 Tactical Analysis for OverallSynthetic Efficiency 1
1.3 Methodological Improvements 2
1.3.1 Chemistry 3
1.3.2 Protecting Group Manipulations 4
1.3.3 Modulationof the Reactivity ofGlycosyl Donors 6
1.3.4 Block Synthesis 8
1.4 Accessibility 11
1.4.1 Solution-basedChemistry 11
1.4.2 One-Pot Glycosylation 13
1.4.3 Solid-PhaseChemistry 16
1.4.3.1 Fundamentals of Solid-PhaseOligosaccharideSynthesis 16
1.4.3.2 The Support 16
1.4.3.3 Linkers tothe Support 20
1.4.3.4 Protecting Groups usedin Solid-PhaseOligosaccharideSynthesis 20
1.4.3.5 Solid-PhaseOligosaccharideSynthesis 20
1.4.3.6 MonitoringofReactionProgress 26
1.4.4 Automation 29
1.5 Concluding Remarks 32
1.6 References 33
2 ComplexCarbohydrate Synthesis 37
Makoto Kiso, Hideharu Ishida,and HiromuneAndo
2.1 Introduction 37
2.2 Synthetic Gangliosides 38
2.2.1 GangliosidesGM4 and GM3, and their Analogues and Derivatives 38
Carbohydrate-basedDrugDiscovery.EditedbyChi-HueyWong
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30632-3
VI Contents
2.2.2 Sialylparagloboside (SPG) Analogues and Derivatives 40
2.2.3 Selectin Ligands 43
2.2.3.1 Sialyl Lewisx 44
2.2.3.2 Novel 6-Sulfo sLex Variants 45
2.2.4 Siglec ligands 46
2.2.4.1 Chol-1 ((cid:1)-Series)Gangliosides 47
2.2.4.2 Novel Sulfated Gangliosides 50
2.3 Toxin Receptor 50
2.4 Summary and Perspectives 52
2.5 References 52
3 TheChemistryofSialicAcid 55
Geert-Jan Boons and AlexeiV. Demchenko
3.1 Introduction 55
3.2 Chemical and Enzymatic Synthesis of Sialic Acids 56
3.3 Chemical Glycosidation ofSialic Acids 59
3.3.1 DirectChemical Sialylations 60
3.3.1.1 2-ChloroDerivativesas Glycosyl Donors 61
3.3.1.2 2-Thio DerivativesasGlycosyl Donors 62
3.3.1.3 2-Xanthates as Glycosyl Donors 69
3.3.1.3 2-Phosphites as Glycosyl Donors 71
3.3.1.4 MiscellaneousDirect Chemical Methods 71
3.3.2 Indirect Chemical Methods with the Useofa Participating Auxiliary
at C-3 73
3.3.2.1 3-Bromo-and other3-O-Auxiliaries 73
3.3.2.2 3-Thio and 3-SelenoAuxiliaries 74
3.3.3 Synthesis of (2(cid:1)8)-Linked Sialosides 77
3.4 Enzymatic Glycosidationsof Sialic Acids 83
3.4.1 Sialyltransferases 84
3.4.1.1 MetabolicEngineering ofthe Sialic AcidBiosynthetic Pathway 90
3.4.2 Sialidases 90
3.5 Synthesis of C- and S-Glycosidesof SialicAcid 91
3.6 Modificationsat N-5 94
3.7 References 95
4 Solid-PhaseOligosaccharide Synthesis 103
PeterH.Seeberger
4.1 Introduction 103
4.2 Pioneering Effortsin Solid-Phase OligosaccharideSynthesis 104
4.3 Synthetic Strategies 105
4.3.1 Immobilization ofthe Glycosyl Acceptor 106
4.3.2 Immobilization ofthe Glycosyl Donor 106
4.3.3 Bi-directionalStrategy 107
4.4 Support Materials 107
4.4.1 Insoluble Supports 107
Contents VII
4.4.2 Soluble Supports 108
4.5 Linkers 108
4.5.1 Silyl Ethers 108
4.5.2 Acid-and Base-LabileLinkers 109
4.5.3 ThioglycosideLinkers 110
4.5.4 Linkers Cleavedby Oxidation 110
4.5.5 PhotocleavableLinkers 111
4.5.6 Linkers Cleavedby OlefinMetathesis 111
4.6 Synthesis of Oligosaccharideson SolidSupport by Useof Different
Glycosylating Agents 112
4.6.1 1,2-Anhydrosugars – The Glycal Assembly Approach 112
4.6.2 Glycosyl Sulfoxides 113
4.6.3 Glycosyl Trichloroacetimidates 114
4.6.4 Thioglycosides 115
4.6.5 Glycosyl Fluorides 118
4.6.6 n-Pentenyl Glycosides 118
4.6.7 Glycosyl Phosphates 118
4.7 Automated Solid-PhaseOligosaccharideSynthesis 118
4.7.1 Fundamental Considerations 119
4.7.2 Automated Synthesis with Glycosyl Trichloroacetimidates 121
4.7.3 Automated Synthesis with Glycosyl Phosphates 121
4.7.4 Automated OligosaccharideSynthesis by Useof DifferentGlycosylating
Agents 121
4.7.5 “Cap-Tags” to SuppressDeletion Sequences 123
4.7.6 Current State of the Art ofAutomated Synthesis 123
4.8 Conclusionand Outlook 124
4.9 References 125
5 SolutionandPolymer-SupportedSynthesisofCarbohydrates 129
Shin-Ichiro Nishimura
5.1 Introduction 129
5.2 Mimicking Glycoprotein Biosynthetic Systems 130
5.3 References 136
6 EnzymaticSynthesisofOligosaccharides
Jianbo Zhang, JunShao, PrezemkKowal, and Peng GeorgeWang
6.1 Introduction 137
6.2 Sugar Nucleotide Biosynthetic Pathways 140
6.2.1 BasicPrinciple 140
6.2.2 Regeneration Systemsfor nine CommonSugar Nucleotides 142
6.2.2.1 Regeneration Systemsfor UDP-Gal, UDP-Glc, UDP-GlcA
and UDP-Xyl 142
6.2.2.2 Regeneration Systemsfor UDP-GlcNAc and UDP-GalNAc 144
6.2.2.3 Regeneration Systemsfor GDP-Man and GDP-Fuc 147
6.2.2.4 CMP-Neu5Ac Regeneration 149
VIII Contents
6.2.3 Novel Energy Sourcein Sugar Nucleotide Regeneration 150
6.3 Enzymatic OligosaccharideSynthesis Processes 151
6.3.1 Cell-FreeOligosaccharideSynthesis 151
6.3.1.1 Immobilized Glycosyltransferasesand Water-Soluble Glycopolymer 152
6.3.1.2 “Superbeads” 154
6.3.2 Large-Scale Syntheses ofOligosaccharideswith Whole Cells 156
6.3.2.1 Kyowa Hakko’s Technology 157
6.3.2.2 Wang’s “Superbug” 157
6.3.2.3 Other Whole Cell-Based Technologies 161
6.4 Future Directions 162
6.5 References 162
7 Glycopeptides andGlycoproteins: SyntheticChemistryandBiology 169
OliverSeitz
7.1 Introduction 169
7.2 The Glycosidic Linkage 169
7.3 The Challenges of Glycopeptide Synthesis 171
7.4 Synthesis of PreformedGlycosyl Amino Acids 173
7.4.1 N-Glycosides 173
7.4.2 O-Glycosides 176
7.4.2.1 O-Glycosyl Amino Acidsbearing Mono-orDisaccharides 176
7.4.2.2 O-Glycosyl Amino Acidsbearing Complex Carbohydrates 179
7.5 Synthesis of Glycopeptides 181
7.5.1 N-Glycopeptide Synthesis in Solution 181
7.5.2 O-Glycopeptide Synthesis in Solution 185
7.5.3 Solid-PhaseSynthesis ofN-Glycopeptides 188
7.5.4 Solid-PhaseSynthesis ofO-Glycopeptides 192
7.6 Biological and Biophysical Studies 200
7.6.1 ConformationsofGlycopeptides 200
7.6.2 Glycopeptides as SubstratesofEnzymes and Receptors 203
7.6.3 Glycopeptides and Cancer Immunotherapy 204
7.6.4 Glycopeptides and T Cell Recognition 206
7.7 Summary and Outlook 208
7.8 References 209
8 SynthesisofComplex Carbohydrates:Everninomicin 13,384-1 215
K.C. Nicolaou, HelenJ. Mitchell,and Scott A.Snyder
8.1 Introduction 215
8.2 Retrosynthetic Analysis and Strategy 218
8.2.1 OverviewofSynthetic Strategies and Methodologies 218
8.2.2 Retrosynthetic Analysis: OverallApproach 222
8.3 Total Synthesis ofEverninomicin13,384-1 (1) 223
8.3.1 ApproachesTowardsthe A B(A)C Fragment 223
1
8.3.1.1 Initial ModelStudies 223
8.3.1.2 Constructionofthe Building Blocks 225
Contents IX
8.3.1.3 Assembly and Completion of the A B(A)C Fragment 229
1
8.3.2 Constructionofthe FGHA Fragment 231
2
8.3.2.1 FirstGenerationApproach to the FGHA Fragment 231
2
8.3.2.2 SecondGenerationStrategy Towardsthe FGHA Fragment 232
2
8.3.2.3 Assembly ofthe FGHA Fragment 235
2
8.3.3 Constructionofthe DE Disaccharide 241
8.3.3.1 Retrosynthetic Analysis and Constructionof Building Blocks
forthe DE Fragment 241
8.3.3.2 Assembly ofthe DE Fragment 243
8.3.3.3 Test of Strategies 244
8.3.4 Assembly ofthe DEFGHA Fragment 245
2
8.3.5 Completion of the Total Synthesis ofEverninomicin13,384-1 247
8.4 Conclusion 249
8.5 References 250
9 ChemicalSynthesisofAsparagine-LinkedGlycoprotein Oligosaccharides:
RecentExamples 253
YukishigeIto and Ichiro Matsuo
9.1 Introduction 253
9.2 Synthesis of Asn-LinkedOligosaccharides:Basic Principles 257
9.3 Chemical Synthesis of Complex Oligosaccharides 261
9.3.1 ClassicalExamples 261
9.3.2 TrichloroacetimidateApproach to Complex-Type Glycan Chains 265
9.3.3 n-Pentenyl Glycosidesas Glycosyl Donors 265
9.3.4 Glycal Approach to Complex Oligosaccharides 267
9.3.5 Intramolecular Aglycon DeliveryApproach 269
9.3.6 New Protecting Group Strategy 273
9.3.7 LinearSynthesis ofBranched Oligosaccharide 274
9.3.8 Chemoenzymatic Approach to Complex-type Glycans 275
9.4 References 278
10 ChemistryandBiochemistry ofAsparagine-LinkedProteinGlycosylation 281
Barbara Imperialiand Vincent W.-F. Tai
10.1 Protein Glycosylation 281
10.1.1 Introduction 281
10.1.2 Asparagine-Linked Glycosylation and Oligosaccharyl Transferase 281
10.2 Small-Molecule Probesof the Biochemistry
ofOligosaccharyl Transferase 283
10.2.1 Photoaffinity and Affinity Labeling of Oligosaccharyl Transferase 284
10.2.2 Investigation ofPeptide-BasedSubstrateAnalogues as Inhibitors
ofOligosaccharyl Transferase 287
10.2.2.1 Inhibitorsof N-LinkedGlycosylation and Glycoprotein Processing 287
10.2.2.2 Peptide-BasedAnalogues and Inhibitors 288
10.2.2.3 Interim Summary 292
X Contents
10.2.3 Investigation ofCarbohydrate-BasedSubstrateAnalogues as Probes
ofOligosaccharyl TransferaseFunction 292
10.2.3.1 PossibleMechanismsforGlycosyl Transfer 294
10.2.3.2 Probingofthe Mechanism ofOligosaccharyl Transferase
with Potential Inhibitors 296
10.2.3.3 Interim Summary 300
10.3 Conclusions 301
10.4 References 301
11 Conformational AnalysisofC-GlycosidesandRelatedCompounds:
ProgrammingConformational ProfilesofC-andO-Glycosides 305
PeterG. Goekjian, AlexanderWei,and Yoshito Kishi
11.1 Introduction 305
11.2 StereoelectronicEffectsand the exo-AnomericConformation 306
11.3 ConformationalAnalysis ofC-Glycosides:
C-Monoglycosides 309
11.4 1,4-LinkedC-Disaccharides:the Importance
ofsyn-Pentane Interactions 314
11.5 Predictionof ConformationalPreference
and Experimental Validation 318
11.6 Programming OligosaccharideConformation 322
11.7 ConformationalDesign ofC-Trisaccharidesbasedon a Human Blood
Group Antigen 323
11.8 ConformationalDesign: Relationship to BiologicalActivity 330
11.8.1 C-Lactosevs.O-Lactose 331
11.8.2 Human BloodGroup Trisaccharides 334
11.9 Concluding Remarks 336
11.10 Acknowledgements 337
11.11 References 337
12 SyntheticLipidAAntagonists forSepsisTreatment 341
WilliamJ. Christ,Lynn D. Hawkins, MichaelD. Lewis,and Yoshito Kishi
12.1 Background 341
12.2 Hypothesisand Approach 342
12.2.1 MonosaccharideAntagonists: Lipid XAnalogues 343
12.2.2 DisaccharideAntagonist ofLipid A: FirstGeneration 344
12.2.3 DisaccharideAntagonist ofLipid A: SecondGeneration 348
12.3 Conclusion 351
12.4 Acknowledgement 353
12.5 References 353
13 Polysialic AcidVaccines 357
Harold J. Jennings
13.1 Introduction 357
13.2 Group C MeningococcalVaccines 358
